vascular leakage

14,15-Leukotriene D4 (14,15-LTD4) is a member of an alternate class of LTs synthesized by a pathway involving the dual actions of 15- and 12-lipoxygenases (15- and 12-LOs) on arachidonic acid via 15-HpETE and 14,15-LTA4 intermediates. 14,15-LTD4 is classified as an eoxin (EXD4), because it is formed mostly by eosinophils. However, mast cells and nasal polyps can synthesize 14,15-LTD4 as well. Little is known about the physiological actions of 14,15-LTD4. It has weak contractile activity on both guinea pig ileum and pulmonary parenchyma in contrast to the effects of 5-LO-derived LTs. However, in an in vitro permeability assay, 14,15-LTD4 can increase vascular permeability of human endothelial cell monolayers, with similar potency to that of 5-LO-derived LTs, resulting in plasma leakage, a hallmark of inflammation.

PF-04577806 is a potent, selective, and ATP competitive inhibitor of the protein kinase C (PKC). It exhibits significant inhibitory activity against various isoforms of PKC, including PKCα, PKCβI, PKCβII, PKCγ, and PKCθ, with IC50 values of 2.4 nM, 8.1 nM, 6.9 nM, 45.9 nM, and 29.5 nM, respectively. Furthermore, PF-04577806 has the ability to reverse retinal vascular leakage in diabetic rats.

PMX-53, a macrocyclic complement 5a (C5a) peptidomimetic and C5a receptor antagonist (IC50 = 0.3 µM), effectively inhibits the C5a-induced secretion of myeloperoxidase (MPO) in isolated human polymorphonuclear leukocytes (PMNs). Administered orally at 10 mg/kg, PMX-53 mitigates vascular leakage, PMN infiltration, and the production of TNF-α and IL-6 in a rat peritoneal Arthus reaction model. Additionally, in a 3-nitropropionic acid (3-NP)-induced Huntington’s disease rat model, it alleviates body weight loss, anorexia, and striatal degeneration. Furthermore, at a dose of 3 mg/kg, PMX-53 decreases atherosclerotic lesion size and lipid content in ApoE-/- mice.

CU06-1004 (Sac-1004) is an orally active compound that acts as an endothelial dysfunction blocker. It mitigates endothelial dysfunction by inhibiting hyperpermeability and inflammation. The compound demonstrates efficacy in reducing vascular leakage and inflammation across multiple animal models, including those for diabetic retinopathy, stroke, cancer, and inflammatory bowel disease. Additionally, CU06-1004 improves conditions in a CDAA-induced mouse model of NASH and enhances cardiac function [1] [2] [3].

Leukotriene C4 (14,15-LTC4) is an inflammatory mediator synthesized from arachidonic acid through the actions of 15- and 12-lipoxygenases (LOs), involving intermediates such as 15-HpETE and 14,15-LTA4. Unlike the majority of leukotrienes formed via the 5-LO pathway, 14,15-LTC4 is an eoxin predominantly produced by eosinophils, although mast cells and nasal polyps can also synthesize it. While its physiological roles are not well understood, 14,15-LTC4 exhibits limited contractile activity on guinea pig ileum and pulmonary parenchyma. However, it can increase vascular permeability in human endothelial cell monolayers in vitro with potency comparable to 5-LO-derived leukotrienes, contributing to plasma leakage characteristic of inflammation.

Sozinibercept (OPT 302; VGX-300) is a soluble form of Vascular Endothelial Growth Factor Receptor-3 (VEGFR-3) that potently inhibits the activity of Vascular Endothelial Growth Factor-C and -D (VEGF-C/D), key proangiogenic factors involved in promoting angiogenesis and vascular leakage. Additionally, Sozinibercept has been shown to inhibit diabetic retinal edema in rats [1] [2] [3].

Abicipar pegol (AGN-150998, MP0112), an anti-VEGF DARPin molecule, represents a novel class of small ankyrin repeat domain-containing proteins designed for high specificity and affinity targeting. This compound is adept at inhibiting angiogenesis and vascular permeability. It has seen applicative use in ocular inflammation-related disease studies through intravitreal injections, notably decreasing mean retinal thickness and leakage area [1] [2].

Ethyl 3,4-dihydroxybenzoate (EDHB): a prolyl hydroxylase inhibitor attenuates acute hypobaric hypoxia mediated vascular leakage in brain.

Diprotin A (Ile-Pro-Ile) (Ile-Pro-Ile) is a dipeptidyl peptidase IV (DPP-IV) inhibitor.